DDX5 promotes oncogene C3 and FABP1 expressions and drives intestinal inflammation and tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA510109 | ENA |
REPOSITORIES: ENA
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Project description:Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid–binding protein 1. However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and fatty acid–binding protein 1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate–induced col- itis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.
2020-08-14 | GSE123881 | GEO
Project description:Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that an RNA binding protein DDX5 augments C3 and FABP1 expressions post-transcriptionally to promote tumorigenesis in the colon and small intestine, respectively. Mice with epithelial-specific knockout of DDX5 are protected from intestine tumorigenesis. The identification of DDX5 as the common upstream regulator of tissue-specific oncogenic molecules provides a new therapeutic target for intestine cancers.
2020-08-12 | GSE124023 | GEO
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Project description:The Asp-Glu-Ala-Asp (DEAD)-box RNA binding protein, DDX5, is ubiquitously expressed in many cell types, yet its role in RNA metabolism and its downstream function in vivo has not been fully elucidated. In the intestine, DDX5 is highly expressed in the intestinal epithelial cell (IECs) and contributes to tumorigenesis. Here, we used a conditional mouse lines where DDX5 is knocked out in IECs upon Tamoxifen administration to uncover mechanisms underlying DDX5 functions in colon tumors.
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Project description:Prep1 is a tumor-suppressor, whereas Meis1 is an oncogene. We show that to perform these activities in MEFs both proteins competitively hetero-dimerize with Pbx1. Meis1 alone transforms Prep1-deficient fibroblasts while Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can therefore alternatively act as oncogene or tumor-suppressor. Prep1 post-translationally controls the level of Meis1 decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth promoting DNA binding landscape of Meis1 to the growth controlling landscape of Prep1. Hence the key feature of Prep1 tumor inhibiting activity is the control of Meis1 stability. Examination of Prep1 and Meis1 in three cell type
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Project description:Prep1 is a tumor-suppressor, whereas Meis1 is an oncogene. We show that to perform these activities in MEFs both proteins competitively hetero-dimerize with Pbx1. Meis1 alone transforms Prep1-deficient fibroblasts while Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can therefore alternatively act as oncogene or tumor-suppressor. Prep1 post-translationally controls the level of Meis1 decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth promoting DNA binding landscape of Meis1 to the growth controlling landscape of Prep1. Hence the key feature of Prep1 tumor inhibiting activity is the control of Meis1 stability. Examination of Prep1 and Meis1 in two cell types
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Project description:The small heat shock protein Hsp27 has been long demonstrated as a major driver of Castration Resistant Prostate Cancer (CRPC) progression via an androgen receptor-independent pathway. In the light of identification of its molecular mechanisms, we found that the RNA helicase protein DDX5 was an interactor of Hsp27 and DDX5 expression was regulated by Hsp27 through its cytoprotective function. We showed that DDX5 was overexpressed in a large collection of human samples in aggressive PCs, especially CRPC. Here, we described the protein-protein interaction network of DDX5 which were identified in four human prostate cell lines (PNT1A, LNCaP, DU-145 and PC-3) representing different disease stages using immunoaffinity purification and quantitative mass spectrometry. The DDX5 interactome in CRPC cells was enriched in several functions (DNA damage response, translation, transcription, RNA stability, and DNA conformation changes) involved in disease progression. Furthermore, we found a new critical function of DDX5 in DNA damage repair in CRPC and validated the interaction of DDX5 with the DNA repair complex Ku70/Ku86 which plays a pivotal role in the NHEJ process. We also showed that DDX5 overexpression conferred resistance to DNA damage poisoners (such as irradiation and cisplatin) in CRPC, a feature that could lead to genome maintenance, tumor progression and treatment resistance.
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